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12.8: Cytoskeletal Dynamics

  • Page ID
    19241
  • In the early development of animals, there is a huge amount of cellular rearrangement and migration as the roughly spherical blob of cells called the blastula starts to differentiate and form cells and tissues with specialized functions. These cells need to move from their point of birth to their eventual positions in the fully developed animal. Some cells, like neurons, have an additional type of cell motility - they extend long processes (axons) out from the cell body to their target of innervation. In both neurite extension and whole cell motility, the cell needs to move first its attachment points and then the bulk of the cell from one point to another. This is done gradually, and uses the cytoskeleton to make the process more efficient. The major elements in cell motility are changing the point of forward adhesion, clearing of internal space by myosin-powered rearrangement of actin microfilaments and the subsequent filling of that space with microtubules.

    For force to be transmitted, the membrane must be attached to the cytoskeleton. In fact, signaling from receptors in the membrane can sometimes directly induce rearrangements or movements of the cytoskeleton via adapter proteins that connect actin (or other cytoskeletal elements) to transmembrane proteins such as integrin receptors. One of the earliest experimental systems for studies of cytoskeleton-membrane interaction was the erythrocyte (red blood cell).

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    Figure 15. Membrane to microfilament linkage complexes in erythrocytes involve spectrin.

    The illustrations above (Figure 15) show some of the interactions of an extensive actin microfilament network with transmembrane proteins. Ankyrin and spectrin are important linkage proteins between the transmembrane proteins and the microfilaments. This idea of building a protein complex around the cytoplasmic side of a transmembrane protein is ubiquitous, and scaffolding (linking) proteins are used not only in connecting the extracellular substrate (via transmembrane protein) to the cytoskeleton, but also to physically connect signaling molecules and thus increase the speed and efficiency of signal transduction.

    Accessory proteins to actinfilaments and microtubules were briefly mentioned earlier. Among other functions, they can control polymerization and depolymerization, form bundles, arrange networks, and bridge between the different cytoskeletal networks. For actin, the primary polymerization control proteins are profilin, which promotes polymerization and thymosin β4, which sequesters g-actin. The minus end capping proteins Arp 2/3 complex and tropomodulin, and the plus end capping proteins CapZ, severin, and gelsolin can stabilize the ends of f-actin. Finally, cofilin can increase depolymerization from the (-) end.

    Profilin has two activities that promote polymerization. First, it is a nucleotide exchange factor that removes ATP bound to g-actin, and replaces it with ADP. This sounds counterintuitive, but keep reading through to the next paragraph. Second, when bound to a g-actin, it increases the rate of addition to actin microfilaments. It does so by binding to the end opposite the ATP-binding site, leaving that site and that side open to binding both ATP and the (+) end of a microfilament. Profilin can be found both in the cytoplasm at large, and associated with phospholipids (PIP2) and membrane proteins, to control such processes as leading edge remodeling of f-actin cytoskeletal structures.

    Thymosin β4 regulates microfilament assembly by controlling the available pool of g-actin. We already stated that greater concentrations of g-actin can increase polymerization rates. However, because of the highly dynamic nature of the actin cytoskeleton, the time constraints of degrading and producing new actin would prevent the fast-response control necessary. Therefore, the optimal mechanism is to maintain a large pool of g-actin monomers, but regulate its availability by tying it up with a sequestering protein - thymosin β4. Thymosin β4 has a 50x higher affinity for g-actin-ATP than for g-actin-ADP, so here is where profilin comes back into the picture. Profilin exchanges the ATP of a Tβ4-g-actin-ATP complex for an ADP. The result is that the Tβ4 releases the g-actin-ADP, allowing it to enter the general pool for building up filaments.

    Increased depolymerization and slowing or cessation of polymerization can gradually break down f-actin structures, but what if there is a need for rapid breakdown? Two of the capping proteins previously mentioned, gelsolin and severin, have an alternate mode of action that can sever actin microfilaments at any point by binding alongside an actin filament and altering the conformation of the subunit to which it is bound. The conformational change forces the actin-actin interaction to break, and the gelsolin or severin then remains in place as a (+) end capping protein.

    Gelsolin is inhibited by the phospholipid PIP2. Phospholipase C, which breaks down PIP2 can also increase cytosolic Ca2+, which is an activator of gelsolin. Thus it is possible to rapidly upregulate gelsolin activity by PLC signaling.

    On the microtubule side of things, due to dynamic instability, one might think that a severing enzyme is not needed, but in fact, spastin and katanin are microtubule-severing proteins found in a variety of cell types, particularly neurons. There is also a Tβ4-like protein for tubulin: Op18, or stathmin, which binds to tubulin dimers (not monomers), acting to sequester them and lower the working concentration. It is regulated by phosphorylation (which turns off its tubulin binding).

    Mutations in spastin are linked to 40% of those spastic paraplegias distinguished by degeneration of very long axons. The severing ability of spastin appears to be required for remodeling of the cytoskeleton in response to neuronal damage.

    Microtubule-associated proteins MAP1, MAP2, and tau (t) each work to promote assembly of microtubules, as well as other functions. MAP1 is the most generally distributed of the three, with tau being found mostly in neurons, and MAP2 even more restricted to neuronal dendrites. These and some other MAPs also act to stabilize microtubules against catastrophe by binding alongside the microtubule and reinforcing the tubulin-tubulin interactions.

    Tau has a complicated biomedical history. Its normal function is clear - assembling, stabilizing, and linking microtubules. However, it is also found in hyperphosphorylated neurofibrillary tangles that are associated with Alzheimer’s disease. A cause for Alzheimer’s is not yet known, so it is still unclear whether the tau protein tangles are play a major role in any of the symptoms.

    Finally, with respect to microfilament and microtubule accessory proteins, there are the linkers. Some of the aforementioned MAPs can crosslink microtubules either into parallel or mesh arrays, as can some kinesins and dyneins, although they are conventionally considered to be motor proteins. On the microfilament side, there are many known proteins that crosslink f-actin, many of which are in the calponin homology domain superfamily, including fimbrin, α-actinin, β-spectrin, dystrophin, and filamin. Although they all can bind to actin, the shape of the protein dictates different types of interaction: for example, fimbrin primarily bundles f-actin in parallel to form bundles, while filamin brings actin filaments together perpendicularly to form mesh networks.

    FG Syndrome is a genetically linked disease characterized by mental retardation, enlarged head, congenital hypotonia, imperforate anus, and partial agenesis of the corpus callosum. It has been linked to mutations in several X chromosome genes, including filamin A (FLNA, FLN1, located Xq28).

    Mutations in dystrophin, which is a major muscle protein of the CD-domain superfamily, can result in Duchenne Muscular Dystrophy or the related but less severe Becker Muscular Dystrophy. The most distinctive feature is a progressive proximal muscular degeneration and pseudohypertrophy of the calf muscles. Onset of DMD is usually recognized before age 3 and is lethal by age 20. However, symptoms of BMD may not present until the 20s, with good probability of long-term survival. Although it is primarily a muscle-wasting disease, dystrophin is present in other cell types, including neurons, which may explain a link to mild mental retardation in some DMD patients. Like FLNA, the dystrophin gene is also located on the X chromosome (Xp21.2).